Phosphatidylinositol-3 (PI-3) kinase has a well-established role in the metabolic and mitogenic actions of insulin and IGF-I. Through cDNA expression screening with a [32p] IRS-1 probe, p55 PIK, a novel class 1A PI-3 kinase: PIK regulatory subunit, was isolated and characterized, p55 mRNA has been shown to be highly expressed in brain and testis, but also is detectable in heart, adipose, kidney, and lung. It is therefore expected that p55PIK will likely play an important role in the cellular insulin response as well as being involved in other important cellular processes. The work proposed in this fellowship will establish the role of p55PlK in the insulin-signaling cascade and more specifically, examine the role of p55 PIK in the regulation of glucose metabolism, neuronal development, and apoptosis. A mouse model system to evaluate these roles in vivo will be developed that involves the targeted deletion of the p55PIK gene through the use of a homologous gene replacement strategy. Because diabetes and its subsequent complications are affecting an increasing number of people worldwide, a complete understanding of the IRS signaling system and its many interacting elements is paramount for the development of new therapeutic targets and alternate approaches for the treatment of patients afflicted with both type 1 and type 2 diabetes.